Promotion of Coronary Collateral Function by Ivabradine-Induced Bradycardia in Patients With Coronary Artery Disease

July 11, 2013 updated by: University Hospital Inselspital, Berne
The purpose of this study in patients with chronic stable coronary artery disease treatable by percutaneous coronary intervention (PCI) is to evaluate the long-term efficacy and safety of the orally taken selective I(f)-inhibitor Ivabradine (Procoralan®, Servier Switzerland) with regard to the promotion of collateral growth.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Coronary artery disease (CAD) is the leading cause of death in industrialized countries. Current therapies for restoration of coronary flow are percutaneous coronary intervention (PCI) or surgical revascularization. However, inherent to them are procedure-related risks and the fact that CAD progression is not prevented. Additionally, up to one fourth of all CAD patients are not amenable to standard revascularization therapies. Thus, there is a need for alternative therapies. Coronary collaterals as natural bypasses are anastomoses without an intervening capillary bed between portions of the same coronary artery or between different coronary arteries. The coronary collateral circulation is prevalent in humans and in CAD the amount of collateral flow is directly related to infarct size, all-cause- and cardiac mortality. Thus, the goal is to promote collateral function in the sense of prophylactic myocardial salvage.

Coronary (collateral) blood flow occurs almost entirely during diastole. Fluid shear stress (FSS) is the driving force in the formation, promotion and maintenance of collaterals (i.e. arteriogenesis). It is the product of blood viscosity and shear rate, the latter being the fluid velocity change between different fluid layers which is related to the fluid velocity at the endothelium. Prolongation of diastole via reduction of resting heart rate (RHR) is naturally equal to extension of shear stress at the endothelium. Bradycardia is likely to be the key factor for augmented collateral function: In several animal models, an inverse relation between heart rate and collateral function was found. We have recently confirmed this finding investigating collateral function measurements in normal coronary arteries of our patient population.

The fact that beta blockers depress contractility and unmask beta-adrenergic coronary vasoconstriction has prompted the development of selective I(f)-inhibitors. To date, ivabradine is the only clinically available specific inhibitor of the pacemaker current in the sinuatrial node (called "funny" current, because of permeability for mixed ions and activation by hyperpolarization instead of depolarization, I(f)). It acts as a pure heart rate lowering agent without affecting blood pressure, myocardial contractility, intra-cardiac conduction, or ventricular repolarization. In contrast to beta blockers or calcium channel blockers, it mimics physiological bradycardia and is therefore appropriate for the purpose of this study. By bradycardization in CAD, ischemia is targeted via reduction of myocardial oxygen demand and increase of oxygen supply without negative inotropic, coronary vasoconstrictive, or metabolic effects. In terms of anti-anginal efficacy, ivabradine has been found to be as effective as atenolol or amlodipine.

Study Type

Interventional

Enrollment (Actual)

43

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Switzerland
      • Bern, Switzerland
        • Bern University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 90 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Age > 18 years old
  2. 1- to 3-vessel stable coronary artery disease (CAD)
  3. At least 1 stenotic lesion suitable for PCI
  4. No Q-wave myocardial infarction in the area undergoing CFI measurement
  5. Written informed consent to participate in the study

Exclusion Criteria:

  1. Acute coronary syndrome
  2. CAD treated best by surgical coronary bypass
  3. Indications for BB treatment (heart failure, arrhythmias, <3months post-infarct)
  4. RHR <60/min without any treatment
  5. Sick sinus syndrome, sinuatrial block or >2nd degree atrio-ventricular block
  6. Atrial fibrillation
  7. Inherited or acquired long-QT syndrome
  8. Indwelling pacemaker
  9. Severe hepatic or renal failure (creatinine clearance <15ml/min)
  10. Hypersensitivity against ivabradine or adjuvants
  11. Pre-menopausal women

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Collateral promotion; PCI after 6 months
Drug: Ivabradine
bid administration of 5mg ivabradine (max 7.5mg) aiming to reduce resting heart rate to 60/min
Other Names:
  • Procoralan, I(f)-inhibitor
Drug: Placebo
bid placebo
Other Names:
  • Placebo control
Experimental: Collateral promotion; PCI at baseline
Drug: Ivabradine
bid administration of 5mg ivabradine (max 7.5mg) aiming to reduce resting heart rate to 60/min
Other Names:
  • Procoralan, I(f)-inhibitor
Drug: Placebo
bid placebo
Other Names:
  • Placebo control

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Collateral flow index (CFI)
Time Frame: 6 months
6 months

Secondary Outcome Measures

Outcome Measure
Time Frame
Myocardial blood flow (MBF) during hyperemia
Time Frame: 6 months
6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital Inselspital, Berne

Investigators

  • Study Chair: Christian Seiler, MD, Prof., University Hospital Inselspital, Berne
  • Principal Investigator: Tobias Traupe, MD, University Hospital Inselspital, Berne
  • Principal Investigator: Michael Stoller, MD, University Hospital Inselspital, Berne

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2009

Primary Completion (Actual)

March 1, 2013

Study Completion (Actual)

March 1, 2013

Study Registration Dates

First Submitted

December 24, 2009

First Submitted That Met QC Criteria

December 24, 2009

First Posted (Estimate)

December 25, 2009

Study Record Updates

Last Update Posted (Estimate)

July 12, 2013

Last Update Submitted That Met QC Criteria

July 11, 2013

Last Verified

July 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 237/2008

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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